Obesity is a major risk factor for the development of cardiovascular diseases including hypertension, but the mechanisms are unclear. Accumulating evidence suggests that increases in sympathetic nerve activity (SNA) play a crucial role in the pathophysiology of obesity-induced hypertension. The rostral ventrolateral medulla (RVLM) is an important brainstem region that regulates SNA to peripheral tissues. Brainstem oxidative stress and neuroinflammation are believed to be important contributors for augmented SNA in obesity. Our objective in this proposal is to determine the molecular mechanisms that are responsible for the initiation and sustenance of the pro-inflammatory milieu in the RVLM contributing to chronic increases in SNA in obesity. Our preliminary data suggests impaired Nrf2 signaling, a key regulator of antioxidant gene expression, along with premature cellular senescence, an irreversible growth arrest in cells as potential contributors to neuroinflammation in the RVLM in obesity. We will test the hypothesis that obesity causes Nrf2 dysfunction and promotes cellular senescence in the RVLM, which in turn contributes to neuroinflammation and increases in SNA. Guided by strong preliminary data, we will test this hypothesis in three aims. 1) Determine the contribution of Nrf2 dysfunction to oxidative stress in the RVLM and its impact on obesity-induced sympathoexcitation. Our working hypothesis, based on our preliminary data, is that obesity causes impairment in Nrf2 signaling in the RVLM leading to increase in oxidative stress and SNA in obesity. 2) Determine the role of senescent cells in RVLM in mediating neuroinflammation and sympathoexcitation in obesity. We postulate that activation of p16-dependent senescence program in the RVLM contributes to neuroinflammation and is responsible for increases in SNA in obesity. We predict that elimination of senescent cells, either through genetic manipulation (p16-3MR mouse model) or by pharmacological means (senolytic drugs), will decrease neuroinflammation and SNA in obesity. 3) Determine the role of Nrf2 dysfunction in initiating the senescence program in the RVLM. Our working hypothesis, based on our preliminary data, is that chronic oxidative stress resulting from Nrf2 dysfunction induces premature senescence in the RVLM. Our work is innovative in that it will be the first to investigate cellular senescence in the brainstem as a mechanism for obesity-induced sympathoexcitation. We will utilize novel transgenic mouse models and state-of-the-art techniques including direct nerve recordings and mouse telemetry system to measure SNA and cardiovascular functions, respectively. We expect that the proposed studies will break new ground in the development of novel interventions against obesity-related cardiovascular risk. In addition, the proposed research will significantly enhance the research environment at Oklahoma State University and offer excellent training opportunities for graduate and undergraduate students in cutting-edge cardiovascular research.